SUMMARY OF WORK: Restenosis is a late complication found in 40-50% of patients undergoing percutaneous transluminal coronary angioplasty (PTCA) for symptomatic coronary artery disease (CAD). It is characterized by neointimal proliferation, which results from vascular smooth muscle cell (VSMC) migration and proliferation, and late vascular remodeling which involves vessel shrinkage and the accumulation of extracellular matrix protein. Coronary stents reduce the incidence of elastic recoil and late vascular remodeling following angioplasty, but remain vulnerable to restenosis because of neointimal hyperplasia. The hyperplastic response triggered by injury is critically dependent on microtubules which are in dynamic equilibrium with their soluble protein constituents, a and b tubulin. The antineoplastic drug, paclitaxel (taxol), inhibits microtubule function by shifting the equilibrium towards the polymerized state. We tested whether paclitaxel will prevent the microtubule-dependent processes involved in neointima formation by deploying paclitaxel-coated Palmaz-Schatz stents in the LAD coronary artery of NIH minipigs and monitoring the vascular response to injury using quantitative coronary angiography and histomorphometry. At 4 weeks post-injury, only the highest dose of mpaclitaxel (187 mg/stent) produced a significant reduction in the angiographic late loss index (LLI) compared to control (p<0.002). These effects were consistent with the decrease in the neointimal area (0 vs 187 mg/stent; p<0.05) and increase in the luminal area (0 vs 187 mg/stent; p<0.003). There were no deaths due to thrombotic complications; however, local effects of toxicity were apparent (focal hemorrhage, medial wall thinning, necrosis) and increased in severity with increasing drug dose. To assess long-term efficacy and safety, a 6 month testing program was established using an expanded range of paclitaxel concentrations bordered by the intermediate (15 mg/stent) and high doses (!87 mg/stent) used in the 4 week study. Of the 40 pigs stented, only one died after 3 months without evidence of thrombosis, aneurysm or rupture of the LAD. Postmortem angiograms from the first 11 pigs sacrificed showed a reduction of late lumenal loss at 30 and 187 mg/stent compared to the control (0 mg/stent). Although final results from the 6 month testing program will not be available until February 1999, preliminary data are encouraging and suggest that significant long-term inhibition of neointimal hyperplasia can achieved by local intravascular delivery without serious complications or regrowth of the neointima.